Allergic disorders are a major global health concern affecting 150 million people worldwide. Recently, epithelial cells have emerged as central participants in the pathogenesis of allergic inflammation: (1) they interface with the environment and initiate the response to environmental triggers; (2) the mucosal epithelium in the lung, skin, and gut functions as a physical barrier against pathogens and environmental exposures including allergens; and (3) epithelial cells have been directly implicated in Th2 responses, serving as a critical interface between innate immune responses and Th2 immunity. The overall objective of these studies is to elucidate the mechanisms by which epithelial cells contribute to the pathogenesis of allergic disorders. The overarching hypothesis of this Center proposal is that epithelial cell genes play a central role in the pathogenesis of allergic disorders. This hypothesis will be tested by three integrated projects that use the Center for coordination and synergistic extension of the projects beyond the scopes and capabilities of the individual projects. This Center will provide important insights into the genes and pathways that may be Important in epithelial driven allergic inflammation and provide a basis for the design of novel therapeutic strategies aimed at the epithelial surface, i.e. lung (asthma), skin (atopic dermatitis), or gut (food allergy or eosinophilic esophagitis). Furthermore, integration of data across projects will provide novel insights into a key question in allergy - What are the mechanisms underlying tissue specific disease manifestations of allergic inflammation? Each project in the Center is focused on distinct epithelial cell genes and their roles in allergic disorders. Project 1 will examine the association of epithelial genes with allergic diseases that target distinct mucosal surfaces. Project 2 will dissect the role of epithelial desmoglein-1 in the pathogenesis of the allergic disorder eosinophilic esophagitis. Project 3 will focus on delineating the mechanisms by which epithelial-derived IL-33 is regulated by trefoil factor 2 (TFF2) during the early innate immune events that initiate allergy and asthma; and better define the role of the TFF2/IL-33 pathway in the pathogenesis of allergic disorders.